Smoking cessation telephone quit lines (QLs), available in all 50 states; now serve over 500,000 smokers each year. On average, only 14% (range: 8% to 20%) of QL callers stop smoking by the 12 month follow-up even with the aid of traditional Cognitive Behavioral Therapy (CBT) combined with pharmacotherapy (typically nicotine replacement therapy; NRT). The low quit rates of QLs stifle their great potential public health impact. To address the low quit rate problem, and thereby start a new research paradigm focused on innovative QL behavioral intervention content, we propose to test a novel counseling approach, called Acceptance & Commitment Therapy (ACT), as a telephone-delivered quit smoking intervention. We recently completed a small (N = 121) NIDA R21 pilot randomized QL trial of proactively-delivered ACT vs. CBT in state QL callers that was underpowered due to R21 budget limits. Results showed that ACT: (1) was feasible to implement and evaluate in a state QL context, (2) had higher participant engagement and satisfaction than CBT, (3) had higher levels of acceptance of cravings than CBT, which in turn predicted quitting smoking, and (4) had higher (albeit non-significant) 6-month post randomization quit rates than CBT. Building on these promising and non- definitive results, a comparative effectiveness randomized trial with a large and fully-powered sample size (N = 1168) and longer term follow-up (i.e., 12 months) is now needed to definitively determine whether telephone- delivered ACT: (1) provides higher quit rates than CBT, (2) operates according to its theory-based mechanisms, and (3) is more cost-effective than CBT. Accordingly, we propose to conduct a randomized comparative effectiveness trial of telephone-delivered ACT counseling plus NRT (n=584) versus telephone-delivered traditional CBT counseling plus NRT (n=584) in state quit line callers, in order to demonstrate that telephone-delivered ACT: (1) has significantly higher 30-day point prevalence abstinence at 12 months post-randomization than telephone-delivered traditional CBT; (2) has smoking cessation outcomes significantly mediated by three psychological processes central to the theoretical model underlying ACT: acceptance of internal (a) sensations, (b) emotions, and (c) thoughts that cue smoking; (3) Will be significantly more cost-effective than telephone-delivered CBT, as measured by cost per additional quitter, incremental cost-effectiveness (ICER), and incremental cost per quality-adjusted life year (QALY). The study, well-motivated by preliminary results, shows exciting promise for improving the success rates of quit lines and thereby lowering healthcare costs and reducing premature tobacco-related deaths. If shown to be efficacious and cost-effective, ACT would provide the scientific field a new conceptual model of QL intervention and quit lines a new treatment approach that could help 45,000 more (of the 500,000) quit line callers to stop smoking each year, thereby saving in medical costs and prolonging lives.